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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C229/38—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to acyclic carbon atoms and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
  • C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
  • C07C323/19—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with singly-bound oxygen atoms bound to acyclic carbon atoms of the carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated

Definitions

• the present invention relates to new chemical compounds which also stimulate soluble guanylate cyclase via a novel mode of action which does not involve the heme group of the enzyme, their production and their use as medicaments, in particular as medicaments for the treatment of cardiovascular diseases.
• Cyclic guanosine monophosphate is one of the most important cellular transmission systems in mammalian cells. Together with nitrogen monoxide ( ⁇ O), which is released from the endothelium and transmits hormone-like and mechanical signals, it forms the ⁇ O / cGMP system.
• the guanylate cyclases catalyze the biosynthesis of cGMP from guanosine triposphate (GTP).
• GTP guanosine triposphate
• the previously known representatives of this family can be divided into two groups according to structural features and the type of ligands: the particulate guanylate cyclases that can be stimulated by natriuretic peptides and the soluble guanylate cyclases that can be stimulated by ⁇ O.
• the soluble guanylate cyclases consist of two subunits and most likely contain one heme per heterodimer, which is part of the regulatory center. This is of central importance for the activation mechanism.
• ⁇ O can bind to the iron atom of the heme and thus significantly increase the activity of the enzyme.
• Hem-free preparations cannot be stimulated by * ⁇ O.
• CO is also able to attack the iron central atom of the heme, whereby the stimulation by CO is significantly less than that by ⁇ O.
• guanylate cyclase plays a decisive role in different physiological processes, in particular in the relaxation and proliferation of smooth muscle cells, platelet aggregation and adhesion and neuronal signal transmission as well as in diseases which are based on a disturbance of the above-mentioned processes.
• the NO / cGMP system can be suppressed in biological conditions, which can lead, for example, to high blood pressure, platelet activation, increased cell proliferation, endothelial dysfunction, atherosclerosis, angina pectoris, heart failure, thromboses, stroke and myocardial infarction.
• a NO-independent treatment option for such diseases aimed at influencing the cGMP signal path in organisms is a promising approach due to the expected high efficiency and few side effects.
• the previously known stimulators of soluble guanylate cyclase stimulate the enzyme either directly via the heme group (carbon monoxide, nitrogen monoxide or diphenyliodonium hexafluorophosphaf) through interaction with the iron center of the heme group and a resulting conformational change that leads to an increase in enzyme activity (Gerzer et al., FEBS Lett. 132 (1981), 71), or via a heme-dependent mechanism which is independent of NO but which potentiates the stimulating effect of NO or CO (e.g. YC-1, Hoenicka et al., J. Mol. Med. (1999) 14; or the pyrazole derivatives described in WO 98/16223, WO 98/16507 and WO 98/23619).
• NO or CO e.g. YC-1, Hoenicka et al., J. Mol. Med. (1999) 14; or the pyrazole derivatives described in WO 98
• the enzyme still shows a detectable catalytic basal activity, i.e. cGMP is still formed.
• the remaining catalytic basal activity of the heme-free enzyme cannot be stimulated by any of the known stimulators mentioned above.
• protoporphyrin IX A stimulation of heme-free soluble guanylate cyclase by protoporphyrin IX has been described (Ignarro et al., Adv. Pharmacol. 26 (1994), 35). However, protoporphyrin IX can be regarded as facial expressions for the NO-heme adduct, which is why the addition of protoporphyrin IX to the soluble guanylate cyclase should lead to the formation of a structure of the enzyme corresponding to the soluble guanylate cyclase stimulated by NO.
• guanylate cyclase can also stimulate guanylate cyclase regardless of the heme group in the enzyme.
• the biological activity of these stimulators is based on a completely new mechanism for stimulating soluble guanylate cyclase.
• the compounds according to the invention are able to stimulate both the heme-containing and the heme-free form of the soluble guanylate cyclase.
• the stimulation of the enzyme with these new stimulators is via a heme-independent path, which is also demonstrated by the fact that the new stimulators on the heme-containing enzyme on the one hand show no synergistic effect with NO and on the other hand the effect of these new stimulators is not affected by Hem-dependent inhibitor of soluble guanylate cyclase, lH-l, 2,4-oxadiazol- (4,3a) -quinoxalin-l-one (ODQ).
• ODQ Hem-dependent inhibitor of soluble guanylate cyclase
• EP-A-0 345 068 describes, inter alia, the ammoalkane carboxylic acid (1) as an intermediate in the synthesis of GABA antagonists:
• WO 93/00359 describes the ammoalkane carboxylic acid (2) as an intermediate in peptide synthesis and its use as an active ingredient for treating diseases of the central nervous system:
• aminoalkanecarboxylic acids of the formula (I) are used for stimulation of the soluble guanylate cyclase which is independent of the heme group present in the enzyme:
• V is absent, O, NR 4 , NR 4 CONR 4 , NR 4 CO, NR 4 SO 2 , COO, CONR 4 or S (O) 0 ,
• R 4 is independent of any further R 4 radical which may be present
• Q is missing, straight chain or branched alkylene, straight chain or branched
• alkenediyl or straight-chain or branched alkynediyl each having up to 12 carbon atoms, each of which has one or more groups from O,
• S (O) p , NR 5 , CO, NR 5 SO 2 or CONR 5 can contain, and one or more times by halogen, hydroxy or alkoxy with up to 4 carbons Substitute atoms can be substituted, optionally any two atoms of the above chain can be connected to form a three- to eight-membered ring,
• R 5 denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms, which can be substituted by halogen or alkoxy having up to 4 carbon atoms,
• p 0, 1 or 2
• NR 7 CONR 7 R 10 or CONR ⁇ R 12 can be substituted
• R 6 is hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, straight-chain or branched haloalkyl having up to to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,
• R 7 independently of any further R 7 radical which may be present, is hydrogen, straight-chain or branched alkyl having up to 8
• R 8 , R 9 , R n and R 12 independently of one another are hydrogen, straight-chain or branched alkyl, straight-chain or branched alkenyl having up to 8 carbon atoms, aryl having 6 to 10 carbon atoms, an aromatic heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O, arylalkyl having 8 to 18 carbon atoms, cycloalkyl having 3 to 8 carbon atoms or a radical of the formula SO 2 R 13 , where the aryl radical in turn is used one or more times by halogen, hydroxy, CN, NO 2 , NH 2 , NHCOR 7 , alkyl, alkoxy, haloalkyl or haloalkoxy with up to 6 carbon atoms can be substituted,
• R 13 denotes straight-chain or branched alkyl having up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, the aryl radical in turn being substituted one or more times by halogen, CN, NO 2 , alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms can or two substituents from R 8 and R 9 or R 11 and R 12 can be bonded to one another to form a five- or six-membered ring which may contain O or N,
• R 10 is hydrogen, straight chain or branched alkyl with up to
• aryl with 6 to 10 carbon atoms, a saturated carbocycle with 6 to 10 carbon atoms, an aromatic or saturated heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O can be substituted, which can also be bonded via N, which is direct or via a group of O, S, SO, SO 2 , NR 7 , SO 2 NR 7 , CONR 7 , straight-chain or branched alkylene, straight-chain or branched Alkenediyl, straight-chain or branched alkyloxy, straight-chain or branched oxyalkyloxy, straight-chain or branched sulfonylalkyl, straight-chain or branched thioalkyl, each with up to 8
• Carbon atoms can be bonded and one to three times by straight-chain or branched alkyl, straight-chain or branched alkoxy, straight-chain or branched alkoxyalkoxy, straight-chain or branched haloalkyl, straight-chain or branched haloalkoxy, carbonylalkyl or straight-chain or branched alkenyl, each with up to 6 Carbon atoms, halogen, SR 6 , CN, NO 2 , NR 8 R 9 , CONR 15 R 16 or NR 14 COR 17 can be substituted,
• R 14 is hydrogen, straight-chain or branched alkyl with up to 8
• R 15 , R 16 independently of one another are hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, cycloalkyl having 3 to 8
• aryl having 6 to 10 carbon atoms or a radical of the formula SO 2 R 18 are carbon atoms, aryl having 6 to 10 carbon atoms or a radical of the formula SO 2 R 18 , the aryl radical in turn being used one or more times by halogen, hydroxy, CN, NO 2 , NH 2 , NHCOR 7 , alkyl, alkoxy, haloalkyl or haloalkoxy can be substituted with up to 6 carbon atoms,
• R 18 denotes straight-chain or branched alkyl having up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, the aryl radical in turn being used one or more times by halogen, hydroxy, CN, NO 2 , NH 2 , NHCOR 7 , alkyl, alkoxy, Haloalkyl or haloalkoxy can be substituted with up to 6 carbon atoms,
• R 17 independently of one another is hydrogen, straight-chain or branched alkyl having up to 12 carbon atoms, straight-chain or branched alkenyl having up to 12 carbon atoms, aryl having 6 to 10 Carbon atoms, an aromatic heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O or cycloalkyl having 3 to 8 carbon atoms, which may also be halogen, hydroxyl, CN, NO 2 , NH 2 , NHCOR 7 , alkyl, alkoxy, haloalkyl or haloalkoxy with up to 6 carbon atoms can be substituted;
• Heteroatoms from the series S, N and / or O can be fused
• SR 17 , SO 2 R 17 optionally substituted by one or two halogen atoms, aryl having 6 to 10 carbon atoms, heteroaryl having 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or
• NHCOR 17 NHSO 2 R 17 NR 17 SOR 17 , NHCONH 2 , NR 17 CONR 17 R 17 , OCONR 17 R 17 , OSO 2 R 17 , C 2 . ⁇ 2 -alkenyl or C 2 - ⁇ 2 -alkynyl, where in addition to one of the above radicals, a radical from the group consisting of hydrogen, halogen, straight-chain or branched alkyl, straight-chain or branched haloalkyl, straight-chain or branched
• R 19 and R 20 independently of one another are hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,
• n an integer from 1 to 4,
• W denotes straight-chain or branched alkylene with up to 6 carbon atoms or straight-chain or branched alkenediyl with up to 6 carbon atoms, each of which can contain a group from O, S (O) q , NR 21 , CO or CONR 21 , or CO, NHCO or OCO means
• q 0, 1 or 2
• R 21 is hydrogen, straight-chain or branched alkyl with up to 8
• U denotes straight-chain or branched alkyl having up to 4 carbon atoms
• A is aryl with 6 to 10 carbon atoms or an aromatic heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O, which may be one to three times by halogen, straight-chain or branched alkyl, straight-chain or branched Haloalkyl, straight-chain or branched alkoxy, haloalkoxy or alkoxycarbonyl with up to 4 carbon atoms, CN, NO 2 or NR 22 R 23 can be substituted,
• R 22 and R 23 each independently represent hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms, carbonylalkyl or sulfonylalkyl,
• Tetrazolyl, COOR 24 or CONR 25 R 26 means
• R 24 is hydrogen, alkyl of 1 to 8 carbon atoms or cycloalkyl of 3 to 8 carbon atoms
• R 25 and R 26 each independently of one another are hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms or a radical of the formula SO 2 R 27 ,
• R 27 denotes straight-chain or branched alkyl having up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, the aryl radical in turn being substituted one or more times by halogen, CN, NO 2 , alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms can
• R 25 and R 26 together form a five- or six-membered ring which may contain N or O
• X denotes straight-chain or branched alkylene with up to 12 carbon atoms or straight-chain or branched alkenediyl with up to 12 carbon atoms, each of one to three groups from O, S (O) r , NR 28 , CO or CONR 29
• aryl or aryloxy with 6 can contain up to 10 carbon atoms, the aryl group in turn being substituted one or more times by halogen, CN, NO 2 , alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms, optionally any two atoms of the above chains by an alkyl chain Formation of a three- to eight-membered ring are connected to one another,
• r 0, 1 or 2
• R 28 is hydrogen, alkyl of 1 to 8 carbon atoms or cycloalkyl
• R 29 denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,
• n 1 or 2;
• R 1 means tetrazolyl, COOR 30 or CONR 31 R 32 ,
• R 30 is hydrogen, alkyl of 1 to 8 carbon atoms or cycloalkyl of 3 to 8 carbon atoms
• R 31 and R 32 each independently represent hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms or a radical of the formula SO 2 R 33 ,
• R 33 means straight-chain or branched alkyl having up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, the aryl radical in turn being used one or more times by halogen, CN, NO 2 , alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms can be substituted
• V missing, O, NR> 4 ", N ⁇ R> 4T-tO- -NMRr>4", N ⁇ RDTO, CO ⁇ O, / C- O-WN ⁇ R ⁇ > 4 4 or S (O) 0 means
• R 4 independently of a further radical R 4 which may be present, denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or arylalkyl having 7 to 18 carbon atoms, the aryl radical in turn being a - or more- can be substituted by halogen, alkyl, alkoxy with up to 6 carbon atoms,
• o 0, 1 or 2
• Q is missing, straight chain or branched alkylene, straight chain or branched
• R 5 denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms, which can be substituted by halogen or alkoxy having up to 4 carbon atoms,
• p 0, 1 or 2
• Y is hydrogen, NR 8 R 9 , aryl with 6 to 10 carbon atoms, an aromatic or saturated heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O or straight-chain or branched cycloalkyl with 3 to 8 carbon atoms, which can also be bonded via N, the cyclic radicals in each case one to three times by straight-chain or branched alkyl, straight-chain or branched alkenyl, straight-chain or branched alkynyl, straight-chain or branched alkoxy, straight- chain or branched alkoxyalkoxy, straight-chain or branched haloalkyl, straight-chain or branched haloalkoxy each with up to 8 carbon atoms, straight-chain or branched cycloalkyl with 3 to 8 carbon atoms, halogen, hydroxy, CN, SR 6 , NO 2 , NR 8 R 9 , NR 7 COR 10
• R 6 is hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, straight-chain or branched haloalkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,
• R 7 independently of any further R 7 radical which may be present, is hydrogen, straight-chain or branched alkyl having up to 8
• R 8 , R 9 , R 11 and R 12 independently of one another are hydrogen, straight-chain or branched alkyl, straight-chain or branched alkenyl having up to 8 carbon atoms, aryl having 6 to 10 carbon atoms, an aromatic heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O, arylalkyl having 8 to 18 carbon atoms, cycloalkyl having 3 to 8 carbon atoms or a radical of the formula SO 2 R 13 , where the aryl radical in turn is used one or more times by halogen, hydroxy, CN, NO 2 , NH 2 , NHCOR 7 , alkyl, alkoxy, haloalkyl or haloalkoxy with up to 6 carbon atoms can be substituted, or two substituents from R 8 and R 9 or R u and R 12 can be bonded to one another to form a five- or six-membered ring which can contain O or
• R 13 denotes straight-chain or branched alkyl having up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, the aryl radical in turn being repeated one or more times
• Halogen, CN, NO 2 , alkyl, alkoxy, haloalkyl or haloalkoxy with up to 6 carbon atoms can be substituted
• R 10 is hydrogen, straight-chain or branched alkyl having up to 12 carbon atoms, straight-chain or branched alkenyl having up to 12 carbon atoms, aryl having 6 to 10 carbon atoms, an aromatic heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O or cycloalkyl having 3 to 8 carbon atoms, which may optionally further be substituted by halogen, hydroxy, CN, NO 2 , NH 2 , NHCOR 7 , alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms;
• R 14 denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,
• R 15 , R 16 independently of one another are hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms or a radical of the formula SO 2 R,
• R 18 denotes straight-chain or branched alkyl having up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, the aryl radical in turn being substituted one or more times by halogen, CN, NO 2 , alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms can
• R 17 is hydrogen, straight-chain or branched alkyl having up to 12 carbon atoms, straight-chain or branched alkenyl having up to 12 carbon atoms, aryl having 6 to 10 carbon atoms, an aromatic heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O or cycloalkyl having 3 to 8 carbon atoms, which may optionally further be substituted by halogen, CN, NO 2 , alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms;
• the cyclic radicals can be fused with an aromatic or saturated carbocycle with 1 to 10 carbon atoms or an aromatic or saturated heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O,
• SR 17 , SO 2 R 17 optionally substituted by one or two halogen atoms, aryl having 6 to 10 carbon atoms, heteroaryl having 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O, cycloalkyl having 3 to 8 carbon atoms , Hydroxy, haloalkoxy with up to 6 carbon atoms, cycloalkoxy with up to 14 carbon atoms,
• R 19 and R 20 independently of one another are hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,
• n an integer from 1 to 4,
• W denotes straight-chain or branched alkylene or straight-chain or branched alkenediyl each having up to 4 carbon atoms
• A is phenyl or an aromatic heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O, which may be one to three times by halogen, straight-chain or branched alkyl, straight-chain or branched haloalkyl or straight-chain or branched Alkoxy with up to 4 carbon atoms can be substituted,
• R 24 is hydrogen or straight-chain or branched alkyl with up to 6
• X denotes straight-chain or branched alkylene with up to 8 carbon atoms or straight-chain or branched alkenediyl with up to 8 carbon atoms, each of which may contain one to three groups from phenyl, phenyloxy, O, CO or CONR 29 , embedded image in which
• R 29 denotes hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms,
• n 1 or 2;
• R 1 means COOR 30 ,
• R 30 is hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms.
• V is absent, O, S or NR 4 means
• R 4 represents hydrogen or methyl
• Q is absent, means straight-chain or branched alkylene with up to 9 carbon atoms or straight-chain or branched alkenediyl or straight-chain or branched alkynediyl with up to 4 carbon atoms, which can be simply substituted by halogen, H, NR 8 R 9 , cyclohexyl, phenyl, naphthyl or a heterocycle from the group
• cyclic radicals are each one to three times by straight-chain or branched alkyl, straight-chain or branched alkenyl, straight-chain or branched alkynyl, straight-chain or branched alkoxy, straight-chain or branched alkoxyalkoxy, straight-chain or branched haloalkyl, straight-chain or branched haloalkoxy, each with up to 4 carbonalkoxy straight-chain or branched cycloalkyl having 3 to 6 carbon atoms, F, CI, Br, I, NO 2 , SR 6 , NR 8 R 9 , NR 7 COR 10 or CONR n R 12 can be substituted,
• R 6 denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, or straight-chain or branched haloalkyl having up to 4 carbon atoms,
• R 7 denotes hydrogen, or straight-chain or branched alkyl having up to 4 carbon atoms
• R 8 , R 9 , R 11 and R 12 independently of one another are hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, or phenyl,
• Methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, methoxy, ethoxy, amino, acetylamino, NO, CF 3 , OCF 3 or CN can be substituted
• R 8 and R 9 or R 11 and R 12 can be bonded to one another to form a five- or six-membered ring which can be interrupted by O or N,
• R 10 denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, or phenyl,
• R 14 denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms
• R 17 is hydrogen, straight-chain or branched alkyl having up to 12 carbon atoms, straight-chain or branched alkenyl having up to 12 carbon atoms, aryl having 6 to 10 carbon atoms, an aromatic heterocycle having 1 to 9 carbon atoms and up to
• cyclic radicals can be fused with an aromatic or saturated carbocycle with 1 to 10 carbon atoms or an aromatic or saturated heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O,
• SR 17 , SO 2 R 17 optionally substituted by one or two halogen atoms, aryl having 6 to 10 carbon atoms, heteroaryl having 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O, cycloalkyl having 3 to 8 carbon atoms , Hydroxyl, haloalkoxy with up to 6 carbon atoms, cycloalkoxy with up to 14 carbon atoms, CONH 2 , CONR 17 R 17 , SO 2 NH 2 , SO 2 NR 17 R 17 , alkoxyalkoxy with up to 12 carbon atoms, alkoxyalkyl with up to 12 carbon atoms , Cycloalkylalkyl with up to 12 carbon atoms, NHCOOR 17 NR 17 COOR 17 , NHCOR 17 , NHSO 2 R 17 NR 17 SOR 17 , NHCONH 2 , NR 17 CONR 17 R 17 ,
• OCONR 17 R 17 , OSO 2 R 17 , C 2 . 12 -Alkenyl or C 2 _ ⁇ 2 -alkynyl means, wherein in addition to one of the above radicals, a radical from the group consisting of hydrogen, halogen, straight-chain or branched alkyl, straight-chain or branched haloalkyl, straight-chain or branched alkoxy, or alkoxycarbonyl each having up to 4 carbon atoms, CN, NO 2 or NR 19 R 20 , can be included;
• R 19 and R 20 independently of one another are hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,
• n an integer from 1 to 4,
• A is phenyl, pyridyl, thienyl or thiazolyl, which is optionally one to three times by methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-
• R 2 means COOR 24
• R 24 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms
• X straight-chain or branched alkylene with up to 8 carbon atoms or straight-chain or branched alkenediyl with up to 8 carbon atoms means, each of which can contain one to three groups of phenyl, phenyloxy, O, CO or CONR 30 ,
• R 30 denotes hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms,
• n 1 or 2;
• R 1 means COOR 35 ,
• R> 35 is hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms.
• Q denotes straight-chain or branched alkylene with up to 9 carbon atoms or straight-chain or branched alkenediyl or straight-chain or branched alkynediyl with up to 4 carbon atoms, which can be simply substituted by halogen, H, cyclohexyl, phenyl or a heterocycle from the group
• cyclic radicals are each one to three times by straight-chain or branched alkyl, straight-chain or branched alkenyl, straight-chain or branched alkynyl, straight-chain or branched alkoxy, straight-chain or branched alkoxyalkoxy, straight-chain or branched haloalkyl, straight-chain or branched haloalkoxy, each with up to 4 carbonalkoxy straight-chain or branched cycloalkyl having 3 to 6 carbon atoms, F, CI, Br, I, NO 2 , SR 6 , NR 8 R 9 , NR 7 COR 10 or CONR ⁇ R 12 can be substituted,
• Wonn R 6 denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, or straight-chain or branched haloalkyl having up to 4 carbon atoms,
• R 7 is hydrogen, or straight-chain or branched alkyl with up to 4
• R 8 , R 9 , R 1 'and R 12 independently of one another are hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, or phenyl, the phenyl radical being mono- to triple by F, CI Br, hydroxy, methyl, ethyl, n Propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, methoxy, ethoxy, amino, acetylamino, NO 2 , CF 3 , OCF 3 or CN can be substituted,
• R 8 and R 9 or R 11 and R 12 can be linked to form a five- or six-membered ring which can be interrupted by O or N,
• R 10 is hydrogen, straight-chain or branched alkyl with up to 4
• R 14 denotes hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms, and
• R 17 is hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, straight-chain or branched alkenyl having up to
• the cyclic radicals can be fused with an aromatic or saturated carbocycle with 1 to 10 carbon atoms or an aromatic or saturated heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O,
• cycloalkyl with 3 to 8 carbon atoms, hydroxy, haloalkoxy with up to 6 carbon atoms, cycloalkoxy with up to 14 carbon atoms,
• NHCOR 17 NHCOR 17 , NHSO 2 R 17 NR 17 SOR 17 , NHCONH 2 , NR 17 CONR 17 R 17 ,
• OCONR 17 R 17 , OSO 2 R 17 , C 2 . 12 -Alkenyl or C 2 . ⁇ 2 -alkynyl means, in addition to one of the above radicals, a radical from the group consisting of hydrogen, halogen, straight-chain or branched alkyl, straight-chain or branched haloalkyl, straight-chain or branched Alkoxy, or alkoxycarbonyl each having up to 4 carbon atoms, CN, NO 2 or NR 19 R 20 , may be included;
• R 19 and R 20 independently of one another are hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,
• n an integer from 1 to 2
• W -CH 2 - or -CH 2 CH 2 - means
• Phenyl means, optionally one to three times by methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, CF 3 , methoxy, ethoxy, F, CI, Br can be substituted
• R 2 means COOR 24
• R 24 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms
• X denotes straight-chain or branched alkylene with up to 6 carbon atoms or straight-chain or branched alkenediyl with up to 6 carbon atoms, each of which can contain one to three groups of phenyloxy, O, CO or CONR 30 , in which R 30 denotes hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms,
• n 1 or 2;
• R 1 means COOR 35 ,
• R> 3 5 is hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms.
• R 1 and R 2 each represent COOH.
• Y is phenyl which is substituted by a radical selected from the group consisting of 2-phenylethyl, cyclohexyl, 4-chlorophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 4-cyanophenyl, 4-chlorophenoxy, 4-methoxyphenoxy, 4-trifluoromethylphenoxy, 4-cyanophenoxy, 4-methylphenyl, 4-methylthiophenyl, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3-mefhoxyphenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-tert. -Butylphenyl,.
• R 3 SR 17 , SO 2 R 17 optionally substituted by one or two fluorine aryl with 6 to 10 carbon atoms, heteroaryl with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O, cycloalkyl with 3 to 8 carbon atoms, hydroxy, haloalkoxy with up to 6 carbon atoms, cycloalkoxy with up to 14 carbon atoms, CONH 2 , CONR 17 R 17 , SO 2 NH 2 , SO 2 NR 17 R 17 , alkoxyalkoxy with up to 12 carbon atoms, alkoxyalkyl with up to 12 carbon atoms, cyclo alkylalkyl having up to 12 carbon atoms, NHCOOR 17 NR 17 COOR 17, NHCOR 17, NHSO 2 R 17 NR l 7 SOR 17, NHCONH 2, NR 17 CONR 17 R 17, OCONR 17 R 17, OSO 2 R 17 , C 2 - ⁇ 2 -alkeny
• R 19 and R 20 independently of one another are hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,
• n an integer from 1 to 2
• U -CH 2 - means A means phenyl
• R 2 means COOH, where R 2 is in the 4-position to the rest U,
• X means (CH 2 ) 4 ,
• R 1 means COOH
• the compounds of the general formula (I) according to the invention can also be present in the form of their salts.
• salts with organic or inorganic bases or acids may be mentioned here.
• Physiologically acceptable salts are preferred in the context of the present invention.
• Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or
• Be sulfonic acids For example, particular preference is given to Salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
• Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group.
• metal or ammonium salts of the compounds according to the invention which have a free carboxyl group.
• Sodium, potassium, magnesium or calcium salts as well as ammonium salts derived from ammonia, or organic amines such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.
• the compounds of the invention can be in stereoisomeric forms, which are either like image and mirror image (enantiomers), or which are not like image and
• the invention relates to both Enantiomers or diastereomers as well as their respective mixtures.
• the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner, for example by racemate resolution or chromatographic separation.
• Double bonds present in the compounds according to the invention can be in the eis or trans configuration (Z or E form).
• Alkyl generally represents a straight-chain or branched hydrocarbon radical having 1 to 20 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl and isooctyl, nonyl, decyl, dodeyl, eicosyl.
• Alkylene generally represents a straight-chain or branched hydrocarbon bridge with 1 to 20 carbon atoms. Examples include methylene, ethylene, propylene, ⁇ -methylethylene, ⁇ -methylethylene, ⁇ -ethylethylene, ß-ethylethylene, butylene, ⁇ -methylpropylene, ß-methylpropylene, ⁇ -methylpropylene, ⁇ -ethylpropylene, ß-ethylpropylene, ⁇ -ethylpropylene, Pentylene, hexylene, heptylene, octylene, nonylene,
• Decylene, dodeylene and eicosylene called.
• Alkenyl generally represents a straight-chain or branched hydrocarbon radical having 2 to 20 carbon atoms and one or more, preferably with one or two, double bonds. Examples include allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, isohexenyl, heptenyl, isoheptenyl, octenyl and isooctenyl.
• Alkynyl generally represents a straight-chain or branched hydrocarbon radical having 2 to 20 carbon atoms and one or more, preferably with one or two triple bonds. Examples include ethynyl, 2-butynyl, 2-pentynyl and 2-hexynyl.
• Alkenediyl generally represents a straight-chain or branched hydrocarbon bridge with 2 to 20 carbon atoms and one or more, preferably with one or two, double bonds.
• Alkenediyl generally represents a straight-chain or branched hydrocarbon bridge with 2 to 20 carbon atoms and one or more, preferably with one or two, double bonds.
• Alkindiyl generally stands for a straight-chain or branched hydrocarbon bridge with 2 to 20 carbon atoms and one or more, preferably with one or two triple bonds. Examples include ethyne-1,2-diyl, propyne-1,3-diyl, 1-butyne-1,4-diyl, 1-butyne-1,3-diyl, 2-butene-1,4-diyl.
• Acyl generally represents straight-chain or branched lower alkyl with 1 to
• Alkoxy generally stands for a straight-chain or branched hydrocarbon est having 1 to 14 carbon atoms which is bonded via an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, heptoxy, isoheptoxy, octoxy or isooctoxy.
• alkoxy and “alkyloxy” are used synonymously.
• Alkoxyalkyl generally represents an alkyl radical with up to 8 carbon atoms which is substituted by an alkoxy radical with up to 8 carbon atoms.
• Alkoxycarbonyl can, for example, by the formula
• Alkyl here generally represents a straight-chain or branched hydrocarbon radical having 1 to 13 carbon atoms. Examples include the following alkoxycarbonyl radicals: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl.
• Cycloalkyl generally represents a cyclic hydrocarbon radical having 3 to 8 carbon atoms. Cyclopropyl, cyclopentyl and cyclohexyl are preferred. Examples include cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
• Cycloalkoxy in the context of the invention is an alkoxy radical whose hydrocarbon radical is a cycloalkyl radical.
• the cycloalkyl radical generally has up to 8 carbon atoms. Examples include: cyclopropyloxy and cyclohexyloxy.
• the terms "cycloalkoxy” and “cycloalkyloxy” are used synonymously.
• Aryl generally represents an aromatic radical having 6 to 10 carbon atoms.
• Preferred aryl radicals are phenyl and naphthyl.
• Halogen in the context of the invention represents fluorine, chlorine, bromine and iodine.
• heterocycle generally represents a saturated, unsaturated or aromatic 3- to 10-membered, for example 5- or 6-membered, heterocycle which can contain up to 3 heteroatoms from the S, N and / or O series and which in the case of a nitrogen atom can also be bound via this.
• Examples include: oxadiazolyl, thiadiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyrrolidinyl, piperazinyl, Tetrahydropyranyl, tetrahydrofuranyl, 1,2,3 triazolyl, thiazolyl, oxazolyl, imidazolyl, morpholinyl or piperidyl.
• heteroaryl stands for an aromatic heterocyclic radical.
• heterocycle structures shown in the present application only one bond to the adjacent group is indicated, e.g. in the case of the heterocycle structures which are suitable for Y, the bond to the unit Q. Irrespective of this, these heterocycle structures can, however, carry further substituents, as indicated.
• the present invention further relates to a process for the preparation of the compounds of the formula (I), characterized in that
• E either represents a leaving group which is substituted in the presence of a base or is an optionally activated hydroxy function
• R 1 , R 2 , R 3 , V, Q, Y, W, X, U, A and m have the same meanings as defined above, E either represents a leaving group which is substituted in the presence of a base or is an optionally activated hydroxy function;
• R 1 , R 2 , R 3 , V, Q, Y, W, X, U, A and m have the same meanings as defined above,
• E either represents a leaving group which is substituted in the presence of a base or is an optionally activated hydroxy function
• E either represents a leaving group which is substituted in the presence of a base or is an optionally activated hydroxy function
• R 3 , V, Q, Y, W, X, U, A and m have the same meanings as defined above,
• R ] b and R 2 b each independently represent CN or COOAlk, where Alk is a straight-chain or branched alkyl radical having up to 6
• R 1 , R 2 , R 3 , V, Q, X, W, U, A and m have the same meanings as defined above,
• L represents Br, I or the group CF 3 SO 2 -O
• M represents an aryl or heteroaryl radical, a straight-chain or branched alkyl, alkenyl or alkynyl radical or cycloalkyl radical or an arylalkyl, an arylalkenyl or an arylalkynyl radical,
• Ar represents an aryl or heteroaryl radical
• R t-Bu
• the compounds of the formula (I) can also be prepared on a solid phase, such as a polystyrene resin, particularly preferably a commercially available Wang polystyrene resin.
• the resin is initially dissolved in a swollen like dimethylformamide (DMF).
• the corresponding carboxylic acid serving as the starting compound is then bound to the resin by standard methods.
• the carboxylic acid can be bound to the resin in the presence of a base such as pyridine or 4-dimethylaminopyridine (DMAP) and a reagent which activates the carboxyl unit, such as an acid halide, for example dichlorobenzoyl chloride, in a solvent such as dimethylformamide (DMF).
• DMAP 4-dimethylaminopyridine
• a reagent which activates the carboxyl unit such as an acid halide, for example dichlorobenzoyl chloride
• DMF dimethylformamide
• other reagents conventionally used for this purpose can also be
• Loading of the solid phase in excess preferably in a two to three-fold excess, is used.
• the carboxylic acid bound to the resin can be derivatized without having to first separate it from the resin.
• a corresponding 4-aminobenzoic acid or 4-formylbenzoic acid derivative can be attached to the resin, then via successive reductive amination reactions as described below for the preparation of the compounds of the formula (II), (IV) and (VI) a compound of formula (VIII) are reacted, which can then be converted into the target compounds on the solid phase analogously to process [D].
• the resin is split off after the desired structure of the target compound on the solid phase in a conventional manner in an acidic environment.
• the product separated from the resin can, after removal of any solvents which may be present, be purified by known cleaning processes, such as, for example, chromatographic processes.
• cleaning processes such as, for example, chromatographic processes.
• Preferred solvents for the processes according to the invention are conventional organic solvents which do not change under the reaction conditions or water.
• ethers such as diethyl ether, butyl methyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene or petroleum ether, or amides such as dimethylformamide or hexamethyl ylphosphorus triamide, or 1,3-dimethyl-imide -on, 1,3-dimethyl-tetrahydro- pyrimidin-2-one, acetonitrile, ethyl acetate or dimethyl sulfoxide can be used. It is of course also possible to use mixtures of the abovementioned solvents.
• the bases preferred for the processes according to the invention comprise basic compounds conventionally used for basic reactions.
• Alkali metal hydrides such as, for example, sodium hydride or potassium hydride, or alkali metal alcoholates such as sodium methoxide, sodium ethanolate, potassium methoxide, potassium ethanolate or potassium t-butoxide, or carbonates such as sodium carbonate, cesium carbonate or potassium carbonate or amides such as sodium amide or lithium diisopropylamide, or organolith such as phenyllithium, butyllithium or methyl lithium or sodium hexamethyldisilazane can be used.
• the processes A to C according to the invention can preferably in acetonitrile in each case by reaction of the compounds (II) and (III), (IV) and (V) or (VI) and (VII) in the presence of a base such as sodium carbonate, Et N, DABCO, K 2 CO, KOH, NaOH or NaH can be carried out.
• the reaction can generally be carried out in a temperature range from -20 ° C. to + 90 ° C., preferably from 0 ° C. to + 70 ° C.
• the reaction can be carried out at normal pressure, elevated or reduced pressure (for example in a range from 0.5 to 5 bar). In general, the reaction is carried out at normal pressure.
• a compound of the formula (I) is obtained by nucleophilic substitution of a leaving group E in one of the compounds of the formula (III), (V) or (VII) by the amine reaction of one of the compounds of the formula (II), (TV) or (VI) shown.
• the following leaving groups E are, for example: halogen, tosylate, mesylate, or a hydroxyl function activated by reagents such as diisopropylazodicarboxylate / PPh 3 (Mitsonobu reaction).
• Process D according to the invention can preferably be carried out in acetonitrile by reaction of the compounds (Vffl) and (IX) in the presence of a base such as sodium carbonate, potassium carbonate, Et 3 N, DABCO, K 2 CO 3 , KOH, NaOH or NaH.
• the reaction can generally be carried out in a temperature range from -20 ° C. to + 90 ° C., preferably from 0 ° C. to + 90 ° C.
• the reaction can be carried out at normal pressure, elevated or reduced pressure (for example in a range from 0.5 to 5 bar). In general, the reaction is carried out at normal pressure.
• a compound of the formula (I) is prepared by nucleophilic substitution of a leaving group E in the compound of the formula (IX) by the hydroxyl or thiol function of the compound of the formula (VIII).
• the following leaving groups E are, for example: halogen, tosylate, mesylate, or a hydroxyl function activated by reagents such as diisopropylazodicarboxylate / PPh 3 (Mitsonobu reaction).
• a compound of the formula (I) in which R 1 and R 2 each represent a free carboxyl function is obtained by converting ester and / or nitrile functions of the compound (X) into the corresponding free carboxyl functions.
• This reaction can be carried out, for example, by adding aqueous solutions of strong acids such as HC1 or H 2 SO 4 , or strong bases such as NaOH, KOH or LiOH.
• the reaction can be carried out in one of the abovementioned organic solvents, in water or in mixtures of organic solvents or in mixtures of organic solvents with water. According to the invention, for example, is preferred
• the reaction can generally be carried out in a temperature range from -20 ° C. to + 90 ° C., preferably from 0 ° C. to + 90 ° C.
• the reaction can be carried out at normal pressure, elevated or reduced pressure (for example in a range from 0.5 to 5 bar).
• the response is
• a compound of the formula (I) is reacted by reacting a compound of the formula (XI) which contains a substitutable group L with a compound of the group (XII) in the presence of a palladium compound and, if appropriate, a reducing agent and other additives represented in basic medium.
• the reaction formally represents a reductive coupling of the compounds of the formulas (XI) and (XII), as described, for example, in LS Hegedus, Organometallics in Synthesis, M. Schlosser, Ed., Wiley & Sons, 1994.
• substitutable group L in the compounds of the formula (XI) for example a halogen radical such as Br or I or a conventional leaving group such as a triflate radical can be used.
• a palladium (II) compound such as Cl 2 Pd (PPh) 2 or Pd (OAc) 2 or a palladium (O) compound such as Pd (PPh 3 ) 4 or Pd (dba) 3 can be used as the palladium compound.
• a reducing agent such as triphenylphosphine or other additives such as Cu (I) Br, NBu 4 NCl, LiCl or Ag 3 PO can also be added to the reaction mixture (cf. T Jeffery, Tetrahedron lett. 1985, 26, 2667 -2670; T. Jeffery, J. Chem. Soc, Chem. Commun. 1984, 1287-1289; S. Bräse, A. deMejiere in "Metal-catalyzed cross-coupling reactions", Ed. F. Diederich, PJ Stang, Wiley-VCH,
• the reaction is carried out in the presence of a conventional base such as Na 2 CO, NaOH or triethylamine.
• Suitable solvents are the organic solvents mentioned above, ethers such as dimethoxyethane being particularly preferred.
• the reaction can generally be in a temperature range from -20 ° C to + 90 ° C, preferably from 0 ° C to + 90 ° C.
• the reaction can be carried out at normal pressure, elevated or reduced pressure (for example in a range from 0.5 to 5 bar). In general, the reaction is carried out at normal pressure.
• the first step of process G thus proceeds analogously to process D, with compounds of formula (XIII) being reacted with the alcohols or thiols of formula (XIII) instead of the compounds of formula (IX).
• the unsaturated compounds of the formula (XIV) are thus obtained, which can be converted into the compounds of the formula (I) by conventional hydrogenation processes.
• Process G can be carried out in one of the above-mentioned organic solvents. Ethyl acetate is preferred.
• the reaction can generally be carried out in a temperature range from -20 ° C. to + 90 ° C., preferably from 0 ° C. to + 90 ° C.
• the reaction can be carried out at normal pressure, elevated or reduced pressure (for example in a range from 0.5 to 5 bar). In general, the reaction is carried out at normal pressure.
• the amines of the formulas II, IV and VI are new and also a subject of the invention.
• the new compounds of the formula II, IN and NI can be obtained in a generally known manner by the following methods:
• radicals R 1 , R 2 , R 3 , m, V, Q, U, W, X, Y and A have the meanings given above;
• Ua, Wa and Xa have the meaning of U, W and X, but are shortened by one carbon unit, and
• T represents hydrogen or a C 1 -C 4 -alkyl function which can also be linked to Ua or Xa to form a cycle
• Va O or S
• the other residues are as defined above.
• (Ilb) can be obtained, for example, by first reacting (XNa) with (XNr ⁇ ) to form a Schiff base and then reducing it with common reducing agents such as ⁇ aBH 4 , H 2 / Pd / C etc. or directly under the conditions of a reductive one Alkylation in the presence of a reducing agent, such as H 2 / Pd / C, NaCNBH 3 or NaH (OAc) 3 .
• a reducing agent such as H 2 / Pd / C, NaCNBH 3 or NaH (OAc) 3 .
• An O or S protective group in (Ilb) or (XXI) can be split off with a suitable reagent (cf. TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, second edition, New York, 1991).
• a suitable reagent cf. TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, second edition, New York, 1991.
• the methyl group can be formed with boron tribromide in methylene chloride at -70 to 20 ° C, with trimethylsilyl iodide in chloroform at 25- Split off at 50 ° C or by sodium ethyl thiolate in DMF at 150 ° C.
• a compound of formula (XXIII) can be obtained from the compound of
• N-protecting group as in (XXII) can be introduced and removed again using conventional methods (cf. TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, second edition, New York, 1991).
• PGn stands for tBuOCO
• the protective group can be removed by reaction of the amine with pyrrocarbonate-tert. Introduce butyl ester in polar or non-polar solvents at 0 ° C to 25 ° C.
• the protecting group can be split off to (Ha) using numerous acids, such as, for example, HC1, H 2 SO 4 or CF 3 COOH, at from 0 ° C. to 25 ° C. (cf. literature cited above).
• Substances of the formulas (III) are commercially available, known from the literature or can be synthesized by processes known from the literature (cf., for example, J. Chem. Soc. 1958, 3065).
• palladium catalysts such as Pd (PPh 3 ) 4 or PdCl 2 (PPh 3 ) 2 and sodium carbonate
• the compounds can also be prepared by generally known methods, e.g. by reacting an alcohol with a chlorination reagent, e.g. Thionyl chloride or sulfuryl chloride can be produced (see e.g. J. March, Advanced Organic Chemistry, fourth edition,
• reduction reactions from aldehyde to alcohol groups, substitutions of alcohol groups by halogen groups, substitutions of halogen functions by nitrile groups, or reductions of nitrile groups to corresponding amino groups can be carried out with all the reactants conventionally used for such reactions (see, for example, the corresponding chapter in March, Advanced Organic Chemistry, Wiley, 3 th ed., 1985).
• This synthetic route can be used, for example, starting from commercially available 2-bromomethyl-4-nitrophenol or commercially available 2-hydroxy-3-nitrobenzoic acid or from the following commercially available or literature-known hydroxycarboxylic acids: Synthesis route c):
• the corresponding hydroxycarboxylic acids or hydroxycarboxylic acid esters can also be used instead of the hydroxyaldehydes.
• the conversion of the primary hydroxy group into the nitrile group can also be carried out via the corresponding bromide, mesylate, tosylate or acetate instead of via the corresponding halide.
• the starting compound can, for example, according to Kessler et. al., tetrahedron
• the starting compound is commercially available.
• the implementation can for example in Tetrahedron Lett. 1990, 1275.
• Amines of the formula (XVI) are commercially available, known from the literature, or can be synthesized analogously to processes known from the literature (cf., for example, J. Am. Chem. Soc. 1982, 104, 6801; Chem. Lett. 1984, 1733; J. Med Chem. 1998, 41, 5219; DE-2059922).
• Amines of the formula (XVII) are commercially available, known from the literature, or can be synthesized analogously to processes known from the literature (see, for example, J. Org. Chem. 1968, 33, 1581; Bull. Chem. Soc. Jpn. 1973, 46, 968 ; J. Am. Chem. Soc. 1958, 80, 1510; J. Org. Chem. 1961, 26, 2507; Synth. Coramun. 1989, 19, 1787).
• Amines of the formulas (XV), (XNI) and (XVII) can also be according to generally known
• Carbonyl compounds of the formula (XVIII) are commercially available, known from the literature, or can be synthesized analogously to processes known from the literature (cf., for example, J. Med. Chem. 1989, 32, 1277; Chem. Ber. 1938, 71, 335; Bull. Soc Chim. Fr. 1996, 123, 679).
• Carbonyl compounds of the formula (XIX) are commercially available, known from the literature, or can be synthesized analogously to processes known from the literature (see, for example, WO96 / 11902; DE-2209128; Synthesis 1995, 1135; Bull. Chem. Soc. Jpn. 1985, 58 , 2192).
• Carbonyl compounds of the formula (XX) are commercially available, known from the literature, or can be synthesized analogously to processes known from the literature (cf. e.g. Synthesis 1983, 942; J. Am. Chem. Soc. 1992, 114, 8158).
• Carbonyl compounds of the formulas (XVIII), (XIX) and (XX) can also be prepared by generally known processes, for example by oxidation of alcohols, the reduction of acid chlorides or the reduction of nitriles (see, for example, J. March, Advanced Organic Chemistry , fourth edition, Wiley, 1992, page 1270 or the literature cited there).
• Compounds of the formula (XII) are commercially available, known from the literature, or can be synthesized analogously to processes known from the literature (see, for example, for aromatic boronic acids: J.Chem.Soc.C 1966, 566. J.Org.Chem., 38, 1973 , 4016; or for tributyltin compounds: Tetrahedron Lett. 31, 1990, 1347).
• the compounds according to the invention in particular the compounds of the general formula (I), show an unforeseeable, valuable spectrum of pharmacological activity.
• the compounds according to the invention lead to vessel relaxation, inhibition of platelet aggregation and to a reduction in blood pressure and to an increase in the coronary blood flow. These effects are mediated by direct stimulation of soluble guanylate cyclase and an intracellular increase in cGMP.
• cardiovascular diseases such as for the treatment of high blood pressure and heart failure, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, of arrhythmias, for the treatment of thromboembolic diseases and ischemia such as myocardial infarction, stroke, transitory and ischemic attacks , peripheral circulatory disorders, prevention of restenosis like after
• Thrombolysis therapies percutaneously transluminal angioplasties (PTA), percutaneously transluminal coronary angioplasties (PTCA), bypass as well as for the treatment of arteriosclerosis, fibrotic diseases such as liver fibrosis or pulmonary fibrosis, asthmatic diseases and diseases of the genitourinary system such as prostate erectile dysfunction, female prostate dysfunction and dysfunctional dysfunction
• PTA percutaneously transluminal angioplasties
• PTCA percutaneously transluminal coronary angioplasties
• bypass bypass as well as for the treatment of arteriosclerosis
• fibrotic diseases such as liver fibrosis or pulmonary fibrosis
• asthmatic diseases and diseases of the genitourinary system such as prostate erectile dysfunction, female prostate dysfunction and dysfunctional dysfunction
• the compounds described in the present invention are also active compounds for combating diseases in the central nervous system which are characterized by disorders of the NO / cGMP system. In particular, they are suitable for eliminating cognitive deficits, for improving learning and memory and for treating Alzheimer's disease. They are also suitable for the treatment of diseases of the central nervous system such as anxiety, tension and depression, central nervous system-related sexual dysfunctions and sleep disorders, as well as for the regulation of pathological disorders in the intake of food, beverages and addictive substances.
• the active ingredients are also suitable for regulating cerebral blood flow and are therefore effective means of combating migraines.
• the compounds according to the invention in particular the compounds of the general formula (I), can likewise be used to combat painful conditions.
• the compounds according to the invention have anti-inflammatory activity and can therefore be used as anti-inflammatory agents.
• Rabbits are anesthetized or killed by intravenous injection of thiopental sodium (approx. 50 mg / kg) and exsanguinated.
• the saphenous artery is removed and divided into 3 mm wide rings.
• the rings are individually mounted on a triangular pair of hooks made of 0.3 mm special wire (Remanium®) that is open at the end.
• Each ring is warmed up in 5 ml organ baths at 37 ° C, brought carbogen-fumigated Krebs-Henseleit solution with the following composition (mM): NaCl: 119; KC1: 4.8; CaCl 2 x 2 H 2 O: 1; MgSO 4 x 7 H 2 O: 1.4; KH 2 PO 4 : 1.2; NaHCO3: 25; Glucose: 10; Bovine serum albumin: 0.001%.
• the contraction force is recorded with Statham UC2 cells, amplified and digitized via A / D converter (DAS-1802 HC, Keithley Instruments Munich), and recorded in parallel on line recorders. Contractions are induced by adding phenylephrine.
• the substance to be examined is added in increasing doses in each further run and the level of the contraction achieved under the influence of the test substance with the level of the last one
• Stasch Purified soluble guanylyl cyclase expressed in a baculovirus / Sf9 System: Stimulation by YC-1, nitric oxide, and carbon oxide. J. Mol. Med. 77 (1999): 14-23.
• the heme-free guanylate cyclase was obtained by adding Tween 20 to the sample buffer (0.5% in the final concentration).
• the present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain the compounds according to the invention, in particular the compounds of the general formula (I), and processes for the preparation of these preparations.
• the active ingredient can optionally also be present in microencapsulated form in one or more of the carriers mentioned above.
• the therapeutically active compounds in particular the compounds of the general formula (I), should be present in the pharmaceutical preparations listed above in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95% by weight of the total mixture to be available.
• the pharmaceutical preparations listed above can also contain further active pharmaceutical ingredients.
• the active ingredient (s) according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg / kg of body weight per 24 hours, optionally in the form multiple doses to achieve the desired results.
• a single dose contains the active ingredient (s) according to the invention preferably in amounts of about 1 to about 80, in particular 3 to 30 mg / kg body weight.
• trimefhylsilylcyanide 0.98 ml (7.3 mmol) trimefhylsilylcyanide are dissolved in 10 ml acetonitrile and with
• reaction mixture is acidified with dilute hydrochloric acid and heated briefly (about 5 minutes) to reflux. After cooling, it is made alkaline with sodium hydroxide solution and extracted with dichloromethane. The organic phase is dried over sodium sulfate. After filtration and spinning in, 1.65 g (98% yield) of a colorless oil are obtained.
• the mixture is acidified to pH 1 with 1-N-HC1 and then adjusted to pH 11 with 1-N- ⁇ aOH solution. After adding 20 ml of water, the mixture is extracted with ethyl acetate, the organic extract is washed with saturated sodium chloride solution and dried over Na 2 SO 4 . After filtration, the solvent is removed in vacuo and the crude product obtained is purified by means of flash chromatography (cyclohexane / ethyl acetate 10: 2). 690 mg (1.28 mmol, 60% yield) of a colorless oil are obtained.

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• 2001
  • 2001-03-07 DE DE10110749A patent/DE10110749A1/de not_active Withdrawn
• 2002
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